US pharmaceutical regulators have granted approval to GlaxoSmithKline's raxibacumab, a monoclonal antibody that is among the only products-and the first biologic product-to be approved through the US Food and Drug Administration's (FDA) animal efficacy rule, better known as the Animal Rule pathway.
The pathway was formed shortly after the terror attacks of 2001, which included a harrowing series of incidents in which spores of anthrax were sent through the US postal system, killing several people and sickening many more.
In response to the attacks, legislators and regulators determined that a regulatory process needed to be established to test the safety and effectiveness of so-called medical countermeasures while taking into account the extremely dangerous nature of the pathogens against which they would need to protect their subjects. The problem, at its most basic level: How can you show that a drug product is safe in humans when subjecting them to a virus or bacteria could potentially kill them?
The answer to that question was, rather simply: You don't. Instead, FDA ultimately established the animal efficacy rule-an approval pathway through which manufacturers can apply for conditional approval of a medical countermeasure based on efficacy testing in human analogues such as pigs or chimpanzees. Safety testing is still conducted in humans.
J&J, GSK Nab First Animal Rule Approvals
In April, Johnson & Johnson's Levaquin (levofloxacin), an antibiotic intended to treat pneumonic plague, became the first product to receive FDA approval via the Animal Rule. That product received approval based on testing in African green monkeys infected with pneumonic plague. None of the placebo control group survived contact with the virus, while 94% of the Levaquin group survived.
FDA's 14 December 2012 approval of raxibacumab marks just the second approval under the Animal Rule, but also the first monoclonal antibody. The drug is also notable in that it is intended to treat inhalation anthrax-the pathogen perhaps most to thank for the formation of the animal efficacy rule.
Raxibacumab was tested in one study involving monkeys and three involving rabbits. As with Levaquin, none of the animals in the control groups survived being infected with inhalation anthrax, while 64% of monkeys and 44% of rabbits in one study treated with raxibacumab survived. FDA also said GSK's studies showed the drug was an improvement over existing antibiotic therapies, according to the animal studies.
Edward Cox, director of FDA's Office of Antimicrobial Products, said that the drug is specifically aimed at defending against another bioterrorism-type event. "Although antibiotics are approved to prevent and treat anthrax infection, raxibacumab is the first approved agent that acts by neutralizing the toxins produced by B. anthracis," he added.
In a statement, GSK said the drug had been in development since the 2001 anthrax attacks. "Our development program charted new territory in terms of the science and the regulatory pathway and was a result of our successful collaboration with the Biomedical Advanced Research and Development Authority (BARDA) and FDA," said Sally Bolmer, senior vice president of Development and Regulatory Affairs at Human Genome Sciences, a subsidiary of GSK.
Other Animal Rule Initiatives
Both approvals come as both FDA and other government entities are looking into ways to refine the Animal Rule process and the protections it affords to the human subjects it is intended to protect.
In May 2012, FDA's chief scientist, Jesse Goodman, noted in a presentation to FDA's Science Board that the agency is planning to launch a program to qualify the animal models used to support animal efficacy rule submissions as part of its larger Medical Countermeasures Initiative. That program might well be its Drug Development Tools Qualification Program (DDTs Program), which it said was specifically geared toward evaluating animal rule qualification tests.
In June 2012, FDA announced it would be accepting a grant application from the University of Texas' Medical Branch to develop a Good Laboratory Practices (GLP) training program to better protect some of the world's most dangerous testing environments-the very same that often contain pathogens like anthrax and the pneumonic plague.
The ethical implications of the pathway are also set to be explored by a high-ranking commission. A June 2012 notice by the Presidential Commission for the Study of Bioethical Issues said that it plans to look at the legal, ethical and societal issues associated with testing medical countermeasures, and particularly how children can be better protected in the case of an emergency.
"While significant progress has been made in the development of medical countermeasures for adults, the development of similar products for children has lagged, in part because of challenges in conducting safety and immunogenicity studies," the Commission explained. "The Commission is particularly interested in policies, practices, research, and perspectives on ethical issues associated with pre- and post-event studies testing the safety, dose, and/or immunogenicity of medical countermeasures for and with children."